Parathyroid hormone (PTH) is known as a hormone that acts on target cells in the kidney and bone to regulate calcium (Ca) and phosphorus (Pi) homeostasis (Non-Patent Document 1). Serum Ca concentration level is maintained by PTH mainly through direct or indirect actions on the gastrointestinal tract, bone, and kidney. PTH promotes resorption of Ca from the renal tubules and thereby suppresses excretion of Ca in the body to the outside. It also increases the synthesis of an enzyme that converts vitamin D to active vitamin D in the kidney, and thereby contributes to the facilitation of active vitamin D-mediated Ca absorption from the gastrointestinal tract. Furthermore, PTH enhances the differentiation of osteoclasts indirectly via osteoblasts and promote Ca release from the bone. These actions of PTH are thought to occur mainly via the cyclic adenosine 3′,5′-monophosphate (cAMP) elevation and/or phospholipase C (PLC) activation that occurs when PTH binds to the PTH1R.
In humans, PTH preparations [PTH (1-34) and PTH (1-84)] have a powerful bone anabolic effect, and induce significant increases in bone mineral density (BMD) and bone strength. Currently, most of the osteoporosis drugs available for humans are inhibitors of bone resorption, and the only type of drug with the bone anabolic effect that, e.g., actively increases BMD is PTH preparations. Thus, PTH preparation is regarded as one of the most effective treatments for osteoporosis (Non-Patent Document 2); however, since it is a peptide, it needs to be administered by an invasive method. Therefore, there is an expectation for production of a pharmaceutical agent that has PTH-like effects and which can be administered non-invasively.
Osteoarthritis is a degenerative disease characterized by degeneration and destruction of cartilage in the joints of the entire body such as knees, hip joints, spine, fingers; synovitis; hardening of the subchondral bone; or joint dysfunction due to osteophyte formation and chronic pain. Forty percent or more of the population aged 65 and older are said to be affected by osteoarthritis, and this has become a huge burden on medical economics (Non-Patent Documents 3 and 4). The causes of osteoarthritis include physically excessive weight load on articular cartilage, inflammation of the synovial membrane and bone marrow, genetic predisposition of the cartilage matrix components, and enhancement of bone metabolism of the subchondral bone; however, there are no therapeutic agents that suppress the degeneration and destruction of articular cartilage, and medical needs remain high.
Aggrecanases (ADAMTS-4, ADAMTS-5, etc.), matrix metalloproteases (MMP-3, MMP-9, MMP-13, etc.; Non-Patent Document 5), and inflammatory cytokines (IL-1, IL-6, etc.; Non-Patent Document 6), which are involved in destruction of the cartilage matrix, have been receiving attention as targets for therapeutic agents, but such agents have not been put to practical use. On the other hand, clinical trials have been carried out for pharmaceutical agents targeting enhancement of metabolic turnover of the subchondral bone (risedronate, calcitonin; Non-Patent Documents 7 and 8); however, degeneration and destruction of articular cartilage could not be suppressed. Furthermore, effects of suppressing destruction of articular cartilage in addition to this mechanism have been demonstrated in clinical trials of strontium ranelate which has the combined effects of promoting bone formation as well as promoting cartilage formation (Non-Patent Document 9); however, it has not reached the stage of practical use.
On the other hand, transformation of articular cartilage from permanent cartilage to calcified cartilage in pathogenesis of osteoarthritis has been reported in recent studies, and its suppression has come to draw attention as a target for therapeutic agents (Non-Patent Document 10). Pharmaceutical agents with multiple modes for suppressing terminal differentiation of articular chondrocytes based on this mechanism of action have been reported to suppress degeneration and destruction of articular cartilage in osteoarthritis model animals, which suggests a possibility of putting therapeutic agents based on this mechanism into practical use (Non-Patent Documents 11 and 12).
Under such circumstances, the present inventors submitted a patent application in advance based on their discovery that the compound represented by formula (A):
[Patent Document 1 may be referred to for W, X, Y, m, n, R1, R2, R33, and R34 in the formula] and pharmacologically acceptable salts thereof are useful as compounds having PTH-like effects, or more preferably, as a PTH1R agonist, and are useful for prevention and/or treatment of osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia, or tumoral calcinosis, or stem cell mobilization (Patent Document 1).
To produce pharmaceutical agents that have high clinical value and can be administered non-invasively, it is necessary to consider the in vivo kinetics such as absorption, distribution, metabolism, and excretion of the drug in addition to its direct actions on the target. For this purpose, it is desirable to have a pharmaceutical agent having PTH-like effects which are high metabolic stability against human liver microsomes and strong human PTH1R-mediated ability of producing cAMP.